This invention broadly relates too heterocyclic carbon compounds having drug and bio-affecting properties and use thereof in a therapeutic process. In particular, the invention concerns 2-alkylthio-adenine derivatives having non-adrenergic smooth muscle relaxant properties making them particularly valuable in overcoming acute bronchospasm and as adjuncts in symptomatic management of chronic, obstructive pulmonary diseases (e.g., asthma, bronchitis, emphysema). Specifically, the invention is concerned with use of the 2-alkylthio-adenine derivatives in a bronchodilating process.
Regarding types of non-adrenergic bronchodilators, the theophylline groups of xanthine derivatives are particularly prominent. For instance, aminophylline, the ethylenediamine salt of theophylline, is an effective bronchodilator which may be administered parenterally, orally, or rectally and is useful in patients where direct relaxation of bronchial muscle is desired. Notwithstanding widespread use, the xanthine class of non-adrenergic bronchodilators have major disadvantages with respect to gastric irritation, cardiovascularand central nervous system side effects. Thus, there is a need for new and effective bronchodilators with increased potency and/or fewer or reduced untoward effects. As shown by standard pharmacological tests, representative compounds of the instant invention have non-adrenergic bronchodilating activity with minimal cardiovascular and central nervous system side effects.
Adenine is 6-aminopurine and purine contains a six-membered pyrimidine ring fused to the five-membered imidazole ring as shown in the following plane formula with the numbering system used herein noted. ##STR1## Various types of purine derivatives are known in which the parent substance purine is substituted at one or more of positions 2, 6, and 9 as illustrated in the following references.
1. K. Kikugawa, et al., Chem. Pharm. Bull., 25 (7), 1811-1821 (1977) describe synthesis of various 2-thioadenine derivatives of the formula ##STR2## wherein inter alia R and R.sub.1 are alkyl, cycloalkyl, etc., as platelet aggregation inhibitors. Specific examples of such compounds include those in which R is propyl or n-hexyl and R.sub.1 is n-hexyl; R and R.sub.1 are cyclopentyl. The authors concluded from the study that the ribosyl moiety of 2-thioadenosine derivatives was essential to the effective inhibition of platelet aggregation and could not be replaced by other substituents.
2. Japanese published application 52-71492 (Farmdoc 53190Y) discloses compounds of the formula ##STR3## wherein R.sub.1 is C.sub.1 --C.sub.10 straight or branched alkyl, C.sub.5 --C.sub.10 cycloalkyl, C.sub.7 --C.sub.11 aralkyl or piperazinoethyl of the formula ##STR4## wherein R.sub.2 is C.sub.7 --C.sub.11 aralkyl, mono-substituted aralkyl, cinnamyl or fluorenyl; R.sub.3 is C.sub.1 --C.sub.10 straight or branched alkyl, C.sub.5 --C.sub.10 cycloalkyl, C.sub.7 --C.sub.11 aralkyl or piperazinoethyl as defined above, with the exclusion of compounds in which R.sub.1 and R.sub.3 are methyl, R.sub.1 is methyl and R.sub.3 is ethyl and R.sub.1 is C.sub.5 --C.sub.10 cycloalkyl and R.sub.3 is C.sub.1 --C.sub.4 alkyl, C.sub.5 --C.sub.10 cycloalkyl or C.sub.7 --C.sub.11 aralkyl. The compounds reportedly show an inhibitory effect on blood platelet aggregation and coronary dilating activity.
3. British Pat. No. 1,493,684 describes S-substituted 2-thioadenosines reportedly useful as platelet inhibitors and coronary vasodilators represented by the formula ##STR5## wherein inter alia R is C.sub.1 --C.sub.10 straight or branched chain alkyl.
4. J. A. Montgomery, et al., J. Am. Chem. Soc., 80 409--411 (1958) describe adenine derivatives of the formula ##STR6## wherein R is n-butyl, cyclopentyl or cyclohexyl as potential anti-cancer agents.
5. H. J. Schaeffer, et al., J. Am. Chem. Soc., 81 197-201 (1959) describe synthesis of compounds having the formula ##STR7## wherein R is 2-hydroxycyclohexyl or 2-cyclohexenyl as potential anti-cancer agents.
6. U.S. Pat. No. 3,917,837 (Lin, et al.) discloses the use of the compound ##STR8## as an anti-inflammatory agent.
7. U.S. Pat. No. 3,862,189 (Schwender) concerns compounds of the formula ##STR9## wherein inter alia, R.sub.1 is amino, alkylamino, aralkylamino, etc.; and R.sub.2 is di-substituted phenylalkyl, tetrahydroquinoylalkyl, etc. useful as antianginal or bronchodilator agents.
8. U.S. Pat. No. 3,930,005 (Wojnar, et al.) discloses compounds of the formula ##STR10## wherein R.sub.1 is hydrogen, halogen, lower alkyl, lower alkoxy, amino, lower alkylamino or di-lower alkylamino and R.sub.2 and R.sub.3 may be hydrogen or lower alkyl as possessing anti-inflammatory activity.
9. Belgian Pat. No. 853,086 (Farmdoc 70719Y) discloses compounds of the formula ##STR11## wherein either X is C.sub.1 --C.sub.6 alkoxy or --NHR; R is H or (lower)alkyl; Y is C.sub.1 --C.sub.6 alkyl, C.sub.3 --C.sub.10 cycloalkyl or hydroxycycloalkyl, phenyl, halophenyl, trifluoromethyl-phenyl, bicycloalkyl or hydroxybicycloalkyl of up to 12 carbons, or --AR.sup.1 ; A is methylene or ethylene; R.sup.1 is phenyl, halophenyl, trifluoromethyl-phenyl, bicycloalkyl or hydroxybicycloalkyl of up to 12 carbons; Q is H, C.sub.1 --C.sub.6 alkyl, C.sub.3 --C.sub.10 cycloalkyl or hydroxycycloalkyl, bicycloalkyl or hydroxybicycloalkyl of up to 12 carbons, phenyl, halophenyl, trifluoromethyl-phenyl or AR.sup.1 ; or X is halogen or (lower)dialkylamino; Y is methyl, ethyl cyclopentyl, phenyl, halophenyl, trifluoromethyl-phenyl or benzyl and Q is as previously defined. The compounds are reported to be useful in treating psoriasis.